We have focused on the pathogenesis of essential hypertension, and have provided evidence that most forms of chronic hypertension are mediated by the development of preglomerular vascular disease with renal ischemia, generation of intrarenal oxidants and vasoconstrictive substances, and sodium retention leading to a shift in the pressure-natriuresis curve. Recently we found that hyperuricemia (which is known to predict the development of hypertension) may engage this pathway. Mild hyperuricemia in rats (created by administering a uricase inhibitor) induces preglomerular arteriolopathy, interstitial renal disease and salt-sensitive hypertension. In this application we further pursue the role of uric acid in hypertension and renal disease by hypothesizing that the arteriolopathy and renal disease induced by uric acid may be mediated by a uric acid-induced systemic and vascular inflammatory response. This hypothesis is based on preliminary studies demonstrating that uric acid can induce monocyte chemoattractant protein (MCP-1) in vascular smooth muscle cells and cytokines by leukocytes. Aim 1 will identify the pathway by which uric acid stimulates MCP-1 in vascular smooth muscle cells by examining the hypothesis that it enters via specific channels (the UAT, OAT3 and URAT1 transporter/exchangers) and that synthesis of MCP-1 is regulated by specific isoforms of protein kinase C and MAP kinases. In Aim 2 we will determine if hyperuricemia initiates systemic and renal inflammation in vivo. Part 1 will test the hypothesis that systemic hyperuricemia in normal rats and in rats with renal disease (remnant kidneys) causes a systemic inflammatory response and that this can be blocked by preventing the development of hyperuricemia with various agents. Part 2 will test the hypothesis that the increased MCP-1 production that occurs in vivo in hyperuricemic rats is responsible for inducing the preglomerular vascular disease and subsequent salt-sensitive hypertension. This will be addressed by blocking studies using a competitive inhibitor analog of MCP-1. These studies may provide important insights into the role of uric acid in hypertension and renal disease. The studies should also provide a potential mechanism to explain why systemic inflammation predicts and causes hypertension.